Substituted omicron-phenylenediamine derivatives, process for their preparation and their use as medicaments

ABSTRACT

The invention relates to new substituted o-phenylenediamine derivatives of the general formula ##STR1## in which R represents optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkinyl, 
     X represents O, S, SO or SO 2  and 
     R 1  and R 2  are different from one another and individually represent ##STR2## in which R 3  and R 4  are identical or different and represent alkyl and 
     R 5  represents hydrogen, optionally substituted alkyl or optionally substituted alkoxy, and salts thereof. 
     Also included in the invention are (1) methods for preparing the above-described compounds, (2) compositions containing the above-described compounds and (3) methods for the treatment of helminthiasis.

This s a continuation of application Ser. No. 845,517 filed Oct. 26, 1977, now abandoned.

The present invention relates to new substituted o-phenylenediamine derivatives, processes for their preparation and their use as medicaments, in particular as anthelmintics.

It has already been disclosed that phenylguanidines of the general formula ##STR3## in which R denotes lower alkyl and

R' denotes both lower alkyl and hydrogen, have anthelmintic actions (for this, see German Offenlegungsschrift (German Published Specification) No. 2,117,293).

According to the present invention, there are provided substituted o-phenylenediamine derivatives of the formula ##STR4## in which R represents optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkinyl,

X represents O, S, SO or SO₂ and

R¹ and R² are different from one another and individually represent ##STR5## in which R³ and R⁴ are identical or different and represent alkyl and

R⁵ represents hydrogen, optionally substituted alkyl or optionally substituted alkoxy, and salts thereof.

The compounds of the invention (i.e. the compounds of the formula I and their salts) exhibit a very good anthelmintic action. Moreover, the anthelmintic action of the compounds of the invention is substantially more pronounced than that of the substituted known phenylguanidines referred to previously. Consequently of the compounds of the invention which are salts, those which are pharmaceutically acceptable are most important and preferred.

It has been found that the compounds of the invention are obtained when phenylamino compounds of the formula ##STR6## in which X, R and R² have the meaning indicated above and in which

X can be linked to position 4 or position 5 of the substituted 1-amino-phenyl group of the formula (II), are reacted with isothioureas of the formula ##STR7## in which R³ and R⁴ have the meaning indicated above and

R⁷ represents alkyl with 1-4 carbon atoms, by methods which are in themselves known in the presence of a diluent and optionally in the presence of an acid.

In addition, it has also been found that the compound of the formula I, or their salts are obtained when compounds of the formula ##STR8## in which R, R¹ and R² have the meaning indicated above, are treated with the corresponding amount of an oxidising agent.

In the case where R¹ represents ##STR9## and R³ and R⁴ denote two non-identical alkyl groups, the compounds of the formula (I) according to the invention can exist in tautomeric forms, as the following example is intended to show: ##STR10##

For reasons for uninformity, in the Application text the particular structural formulae are formulated in the same way in all cases. However, these formulae are to be construed as including all tautomeric forms of the compounds.

If N,N'-bis-methoxycarbonyl-S-methyl-isothiourea and 1-amino-2-acetamido-5-methoxy-benzene are used as the starting materials, the course of the reaction can be represented by the following equation: ##STR11##

If N-(2-formylamino-4-propylthio-phenyl)-N',N''-bis-methoxycarbonyl-guanidine and hydrogen peroxide are used as the starting materials for the reaction of compounds of the formula (V) with oxidising agents, the course of the reaction can be represented by the following equation: ##STR12##

Preferred optionally substituted alkyl groups for the radicals R and R⁵ include straight-chain or branched alkyl groups with 1 to 6, in particular 1 to 4, carbon atoms. Examples which may be mentioned are optionally substituted methyl, ethyl, n- and i-propyl and n-, i-, and t-butyl.

Preferred optionally substituted alkenyl groups for the radical R include straight-chain or branched alkenyl groups with 2 to 6, in particular 2 to 4, carbon atoms. Examples which may be mentioned are optionally substituted ethenyl, propen-1-yl, propen-2-yl and buten-3-yl.

Preferred optionally substituted alkinyl groups for the radical R include straight-chain or branched alkinyl groups with 2 to 6, in particular 2 to 4, carbon atoms. Examples which may be mentioned are optionally substituted ethinyl, propin-1-yl, propin-3-yl and butin-3-yl.

Preferred alkyl groups for the radicals R³ and R⁴ include straight-chain or branched alkyl groups with 1 to 6, in particular 1 to 4, carbon atoms. Examples which may be mentioned are optionally substituted methyl, ethyl, n- and i-propyl and n-, i- and t-butyl.

Preferred alkoxy groups for the radical R⁵ include straight-chain or branched alkoxy groups with preferably 1 to 6, in particular 1 to 4, carbon atoms. Examples which may be mentioned are optionally substituted methoxy, ethoxy, n- and i-propoxy and n-, i- and t-butoxy.

Suitable substituents for the optionally substituted alkyl, alkenyl and alkinyl radical R which may be mentioned are halogen, especially fluorine, chlorine and bromine, cyano, (C₁ -C₄)-alkoxy and (C₁ -C₄)-alkylthio.

Suitable substituents for the optionally substituted alkyl radical R⁵ which may be mentioned are: (C₁ -C₆)-alkoxy, halogen, (C₁ -C₄)-alkylmercapto, cyano, and radicals of the formula ##STR13## in which R⁶ and R⁷ can be identical or different and each represents hydrogen or a (C₁ -C₄)-alkyl group which is optionally substituted by (C₁ -C₄)-alkoxy, trifluoromethyl or cyano, or

in which

the two radicals R⁶ and R⁷, together with the nitrogen atom to which they are attached form a 5-membered, 6-membered or 7-membered heterocyclic ring which can be interrupted by further hetero-atoms (such as N, O and S) and can be saturated or unsaturated.

Examples of individual substituted alkyl, alkenyl or alkinyl radicals R which may be mentioned are: chloropropyl, chlorobutyl, cyanoethyl, cyanopropyl, cyanobutyl, cyanohexyl, bromopropyl, bromobutyl, trifluoromethyl, trifluoroethyl, fluoropropyl, fluorobutyl, 3-chloropropen-2-yl, 2,3-dichloropropen-2-yl, 3-chloro-3-methyl-propen-2-yl, 2-methoxyethyl, 2-ethoxyethyl, 3-methoxypropyl, 2-methylmercaptoethyl, 2-ethylmercaptoethyl and 2-mercaptopropyl.

Examples of individual substituted alkyl radicals R⁵ which may be mentioned are: methoxyethyl, ethoxyethyl, methylmercaptoethyl, ethylmercaptoethyl, methylmercaptopropyl, chloromethyl, chloroethyl, cyanomethyl and cyanoethyl.

Examples of radicals ##STR14## which may be mentioned are: dimethylamino, diethylamino, dipropylamino, pyrrolidinyl, piperidinyl and hexamethyleneiminyl, and examples which may be mentioned for an interruption of the ring by a further hetero-atom such as N, O and S are morpholinyl, thiomorpholinyl, piperazinyl and N-methylpiperazinyl.

Examples of further individual substituted alkyl radicals R⁵ which may be mentioned are: dimethylaminomethyl, dimethylaminoethyl, diethylaminomethyl, diethylaminoethyl, pyrrolidinomethyl, pyrrolidinoethyl, pyrrolidinopropyl, piperidinomethyl, piperidinoethyl, hexamethyleneiminomethyl, hexamethyleneiminoethyl, morpholinomethyl, morpholinoethyl, morpholinopropyl, thiomorpholinoethyl, piperazinomethyl, piperazinoethyl, N-methylpiperazinoethyl and the like.

The thioureas used as starting materials are defined by the formula (III) and are known.

Some of the substituted phenylamino compounds of the formula (II) used as starting materials are not yet known. However, they can be easily prepared analogously to processes known from the literature. Thus, for example, 1-amino-2-acetamido-4-propylthio-benzene is obtained by the following reaction sequence: ##STR15##

1-Amino-2-acetamido-5-butoxy-benzene is obtained, for example, according to the reaction scheme: ##STR16## and 1-amino-2-β-piperidino-acetamido-4-propylthiobenzene is obtained, for example, according to the reaction sequence: ##STR17##

The 2-amino-4-substituted anilides can be prepared by the processes indicated in the following formula scheme, for example: ##STR18##

Diluents which can be used for the reaction of compounds of the formula (II) with isothioureas of the formula (III) include all inert polar organic solvents. These include, preferably, alcohols, preferably alkanols having up to six carbon atoms, such as methanol, ethanol, iso-propanol and their mixtures with water, ketones, such as acetone, methyl ethyl ketone (also mixed with water), but also ethers, such as dioxane or tetrahydrofurane or diethylether, diisopropyl ether.

In principle, the acids added as catalysts which promote the reaction can be chosen as desired from the range of known organic or inorganic acids. However, the easily accessible, industrially important representatives of these classes are advantageously used. Examples which may be mentioned are: hydrochloric acid, sulphuric acid, nitric acid, formic acid, acetic acid and p-toluenesulphonic acid.

The reaction temperatures can be varied within a wide range. In general, the reaction is carried out between about 0° and 120° C., preferably between about 0° and 80° C. In general, the reaction is carried out under normal pressure.

In general, molar amounts are employed when carrying out the reaction of compounds of the formula (II) with those of the formula (III).

In addition to hydrogen peroxide, the following may be mentioned as examples of oxidising agents which can be used for the oxidation of o-phenylenediamine derivatives of the formula (V): organic peracids, such as peracetic acid, performic acid, perbenzoic acid, m-chloroperbenzoic acid and monoperphthalic acid, inorganic peroxides, such as hydrogen peroxide, dissolved in water or dilute organic acids, inorganic oxidising agents, such as chromic acid, nitric acid, potassium permanganate, chlorine, bromine, halogen oxyacids, such as hypochlorous, chlorous, chloric or perchloric acid, tert-butyl hypochlorite, methyl hypochlorite or tert-butyl chromate, or organic N-halogeno compounds, such as N-chlorosuccinimide, N-bromosuccinimide and N-halogenosulphonic acid amides or N-halogenocarboxylic acid amides.

In general, the oxidation of compounds of the formula (IV) to the substances of the formula (I) is carried out in a diluent which is inert towards the reaction, such as, for example, acetic anhydride or acetic acid, at temperatures from about 0°-100° C., preferably at about 20° to 60° C.

By appropriate choice, which in itself is known from the literature, of the oxidising agents and the reaction conditions, the oxidation potential can be accordingly adjusted in each case, so that the oxidation reaction can be controlled to prepare the sulphoxides (compounds of the general formula (IV) in which Z represents SO), or the sulphones (compounds of the general formula (IV) in which Z represents SO₂).

The new compounds can be administered orally and, if they carry a basic centre, also, surprisingly, parenterally, the latter also being used in the form of their physiologically acceptable salts, such as, for example, hydrohalides, preferably hydrochlorides, sulphates, phosphates, nitrates, maleates, fumarates, acetates, methanesulphonates, naphthalenedisulphonates and others.

A resulting basic compound can be converted into a corresponding acid addition salt, for example by reacting it with an inorganic or organic acid, such as therapeutically useful acid, or with a corresponding anion exchange preparation, and isolating the desired salt. An acid addition salt may be converted into the free compound by treatment with a base, e.g. a metal hydroxide, ammonia or a hydroxyl ion exchange preparation. Therapeutically useful acids are, for example, inorganic acids, e.g. hydrochloric, hydrobromic, sulfuric, phosphoric, nitric or perchloric acid, or organic acids, e.g. carboxylic or sulfonic acids, such as formic, acetic, propionic, succinic, glycollic, lactic, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, pyroracemic, phenylacetic, benzoic, 4-aminobenzoic, anthranilic, 4-hydroxybenzoic, salicyclic, aminosalicylic, embonic, nicotinic, methanesulfonic, ethanesulfonic, hydroxy-ethanesulfonic, ethylenesulfonic, benzenesulfonic, halogenbenzenesulfonic, toluensulfonic, naphthalenesulfonic and sulfanilic acid; methionine, tryptophan, lysine and arginine.

These or other salts, for example, the picrates, can also be used for purification of the bases obtained; the bases are converted into salts, the salts are separated and the bases are liberated from the salts. In view of the close relationship between the free compounds and the compounds in the form of their salts, whenever a compound is referred to in this context, a corresponding salt is also intended, provided such is possible or appropriate under the circumstances.

The compounds prepared according to the invention exhibit a surprisingly good and broad action against the following nematodes and cestodes:

1. Hookworms (for example Uncinaria stenocephala, Ancylostoma caninum and Bunostomum trigonocephalum)

2. Trichostrongylidae (for example Nippostrongylus muris, Haemonchus contortus, Trichostrongylus colubriformis and Ostertagia circumcincta)

3. Strongylidae (for example Oesophagostomum columbianum)

4. Rhabditidae (for example Strongyloides ratti)

5. Maw-worms (for example Ascaris suum, Toxocara canis and Toxascaris leonina)

6. Pin-worms (for example Aspiculuris tetraptera)

7. Heterakidae (for example Heterakis spumosa)

8. Whip-worms (for example Trichuris muris)

9. Filariae (for example Litomosoides carinii and Dipetalonema witei)

10. Cestodes (for example Hymenolepis nana, Taenia pisiformis and Echinococcus multilocularis)

11. Trematodes (for example Fasciola hepatica).

Their action was tested in animal experiments after oral and parenteral administration to test animals heavily infected with parasites. The doses used are tolerated very well by the test animals.

The new active compounds can be used as anthelmintics both in medicine.

The present invention provides a pharmaceutical composition containing as active ingredient a compound of the invention in admixture with a solid or liquefied gaseous diluent, or in admixture with a liquid diluent other than a solvent of a molecular weight less than 200 (preferably less than 350) except in the presence of a surface active agent.

The invention further provides a pharmaceutical composition containing as active ingredient a compound of the invention in the form of a sterile or isotonic aqueous solution.

The invention also provides a medicament in dosage unit form comprising a compound of the invention.

The invention also provides a medicament in the form of tablets (including lozenges and granules), dragees, capsules, pills, ampoules or suppositories comprising a compound of the invention.

"Medicament" as used in this Specification means physically discrete coherent portions suitable for medical administration. "Medicament in dosage unit form" as used in this Specification means physically discrete coherent units suitable for medical administration each containing a daily dose or a multiple (up to four times) or sub-multiple (down to a fortieth) of a daily does of the compound of the invention in association with a carrier and/or enclosed within an envelope. Whether the medicament contains a daily dose or, for example, a half, a third, or a quarter of a daily dose will depend on whether the medicament is to be administered once or, for example, twice, three times or four times a day respectively.

The pharmaceutical compositions according to the invention may, for example, take the form of ointments, gels, pastes creams, spray (including aerosols), lotions, suspensions, solutions and emulsions of the active ingredient in aqueous or non-aqueous diluents, syrups, granules or powders.

The diluents to be used in pharmaceutical compositions (e.g. granulates) adapted to be formed into tablets, dragees, caspules and pills include the following: (a) fillers and extenders, e.g. starch, sugars, mannitol, and silicic acid; (b) binding agents, e.g. carboxymethyl cellulose and other cellulose derivatives, alginates, gelatine and polyvinyl pyrrolidone; (c) moisturizing agents, e.g. glycerol; (d) distintegrating agents, e.g. agar-agar, calcium carbonate and sodium bicarbonate; (e) agents for retarding dissolution e.g. paraffin; (f) resorption accelerators, e.g. quaternary ammonium compounds; (g) surface active agents, e.g. cetyl alcohol, glycerol monostearate; (h) adsorptive carriers, e.g. kaolin and bentonite; (i) lubricants, e.g. talc, calcium and magnesium stearate and solid polyethylene glycols.

The tablets, dragees, capsules and pills formed from the pharmaceutical compositions of the invention can have the customary coatings, envelopes and protective matrices, which may contain opacifiers. They can be so constituted that they release the active ingredient only or preferably in a particular part of the intestinal tract, possibly over a period of time. The coatings, envelopes and protective matrices may be made, for example, of polymeric substances or waxes.

The ingredient can also be made up in microencapsulated form together with one or several of the above-mentioned diluents.

The diluents to be used in pharmaceutical compositions adapted to be formed into suppositories can, for example, be the usual water-soluble or water-insoluble diluents, such as polyethylene glycols and fats (e.g. cocoa oil and high esters [e.g. C₁₄ -alcohol with C₁₆ -fatty acid]) or mixtures of these diluents.

The pharmaceutical compositions which are ointments pastes, creams and gels can, for example, contain the usual diluents, e.g. animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide or mixtures of these substances.

The pharmaceutical compositions which are powders and sprays can, for example, contain the usual diluents, e.g. lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder or mixtures of these substances. Aerosol sprays can, for example, contain the usual propellants, e.g. chlorofluorohydrocarbons.

The pharmaceutical compositions which are solutions and emulsions can, for example, contain the customary diluents (with, of course, the above-mentioned exlcusion of solvents having a molecular weight below 200 except in the presence of a surface-active agent), such as solvents, dissolving agents and emulsifiers; specific examples of such diluents are water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils [for example ground nut oil], glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitol or mixtures thereof.

For parenteral administration, the solutions and emulsions should be sterile, and, if appropriate, blood-isotonic.

The pharmaceutical compositions which are suspensions can contain the usual diluents, such as liquid diluents, e.g. water, ethyl alcohol, propylene glycol, surface-active agents (e.g. ethoxylated isostearyl alcohols, polyoxyethylene sorbite and sorbitane esters), microcrystalline cellulose, aluminium methahydroxide, bentonite, agar-agar and tragacanth or mixtures thereof.

All the pharmaceutical compositions according to the invention can also contain colouring agents and preservatives as well as perfumes and flavouring additions (e.g. peppermint oil and eucalyptus oil) and sweetening agents (e.g. saccharin).

The pharmaceutical compositions according to the invention preferably contain about 0.1 to 99.5, more preferably from about 0.5 to 95% of the active ingredient by weight of the total composition.

In addition to a compound of the invention, the pharmaceutical compositions and medicaments according to the invention can also contain other pharmaceutically active compounds. They may also contain a plurality of compounds of the invention.

Any diluent in the medicaments of the present invention may be any of those mentioned above in relation to the pharmaceutical compositions of the present invention. Such medicaments may include solvents of molecular weight less than 200 as sole diluent.

The discrete coherent portions constituting the medicament according to the invention will generally be adapted, by virtue of their shape or packaging, for medical administration and may be, for example, any of the following: tablets, (including lozenges and granules), pills, dragees, capsules, suppositories and ampoules. Some of these forms may be made up for delayed release of the active ingredient. Some, such as capsules, include a protective envelope which renders the portions of the medicament physically discrete and coherent.

The preferred daily dose for administration of the medicaments of the invention is 5 mg to 5 g of active ingredient.

The production of the above-mentioned pharmaceutical compositions and medicaments is carried out by any method known in the art, for example, by mixing the active ingredient(s) with the diluent(s) to form a pharmaceutical composition (e.g. a granulate) and then forming the composition into the medicament (e.g. tablets).

This invention further provides a method of combating (including prevention, relief and cure of) the above-mentioned diseases in human and non-human animals, which comprises administering to the animals a compound of the invention alone or in admixture with a diluent on in the form of a medicament according to the invention.

It is envisaged that these active compounds will be administered perorally, parenterally (for example intramuscularly, intraperitoneally or intravenously, or rectally, preferably orally. Parenteral, especially subcutaneous, administerion and dermal application is also practicable alternatives. The preferred compositions and medicaments are those adapted for oral administration.

In general, it has proved advantageous to administer amounts of about 0.1 to about 50 mg of the new compounds per kg of body weight per day in order to achieve effective results.

Nevertheless, it can at times be necessary to deviate from the amounts mentioned and in particular to do so as a function of the body weight of the test animal or the nature of the method of administration, but also depending on the species of animal and its individual behaviour towards the medicament or its type of formulation and the time or interval at which it is administered. Thus it can in some cases suffice to manage with less than the abovementioned minimum amount whilst in other cases the upper limit mentioned must be exceeded. Where larger amounts are administered it can be advisable to divide these into several individual administrations over the course of the day. The same dosage range is envisaged for administration in human medicine and in veterinary medicine. The general sense of the other comments made above also applies.

The anthelmintic action of the active compounds according to the invention is explained in more detail with the aid of the use examples which follow.

EXAMPLE A Gastric and intestinal worm test/sheep

Sheep experimentally infected with Haemonchus contortus or Trichostrongylus coluoriformis were treated after the end of the pre-patency period of the parasites. The amount of active compound was administered orally as pure active compound in gelatine capsules.

The degree of action is determined by quantitatively counting the worm eggs excreted with the faeces before and after the treatment.

Complete cessation of the excretion of eggs after the treatment means that the worms have been expelled or have been damaged to the point that they can no longer produce eggs (effective dose).

The active compounds tested and effective doses (minimum effective dose) can be seen from the table which follows.

                                      TABLE 1                                      __________________________________________________________________________     (accompanying Example A)                                                                                    Minimum effective                                 Active compound according    dose (reduction) >90%                             to the invention             in mg/kg of body weight                           __________________________________________________________________________      ##STR19##                   Haemonchus cont. 2.5                               ##STR20##                   Trichostrong. col. 2.5                             ##STR21##                   Trichostrong. col. 2.5                             ##STR22##                   Haemonchus cont. 1                                 ##STR23##                   Haemonchus cont. 0.5                               ##STR24##                   Haemonchus cont. 0.5                              Known preparation for comparison "Thiabendazole"                                ##STR25##                   Haemonchus cont. 50 Trichostrong. col. 25         Preparation examples                                                           Example 1                                                                       ##STR26##                                                                     18 g (0.1 mol) of 1-amino-2-acetamido-5-methoxybenzene of melting point        151° C. are boiled, together with 20.6 g (0.1 mol) of                   N,N'-bis-methoxycarbonylisothiourea S-methyl ether and 2.6 g (0.015 mol)       of p-toluenesulphonic acid, in 200 ml of absolute methanol for 3 hours,   

The mixture is then filtered hot and, after cooling, the N-(2-acetamido-5-methoxy-phenyl)-N',N"-bis-methoxycarbonylguanidine which has crystallised out is filtered off, rinsed with ether and dried under a high vacuum, melting point 164° C., yield 20 g=59% of theory.

The yield can be increased by working up the mother liquor.

EXAMPLES 2 to 12

The compounds listed in the following Table were obtained analogously to Example 1.

    __________________________________________________________________________      ##STR27##                                                                     Starting materials      Substances prepared according to the invention         Example          Melting point               Melting point                     No.  R    R.sup.5                                                                             R.sup.2                                                                          °C.                                                                            R    R.sup.5                                                                             R.sup.2    °C.                        __________________________________________________________________________     2    CH.sub.3                                                                            C.sub.2 H.sub.5                                                                     H 118    CH.sub.3                                                                            C.sub.2 H.sub.5                                                                      ##STR28## 167                               3    CH.sub.3                                                                            C.sub.3 H.sub.7 (n)                                                                 H 121    CH.sub.3                                                                            C.sub.3 H.sub.7 (n)                                                                 "          165                               4    C.sub.2 H.sub.5                                                                     CH.sub.3                                                                            H 146    C.sub.2 H.sub.5                                                                     CH.sub.3                                                                            "          173                               5    C.sub.2 H.sub.5                                                                     C.sub.2 H.sub.5                                                                     H 134    C.sub.2 H.sub.5                                                                     C.sub.2 H.sub.5                                                                     "          168                               6    C.sub.2 H.sub.5                                                                     C.sub.3 H.sub.7 (n)                                                                 H 116    C.sub.2 H.sub.5                                                                     C.sub.3 H.sub.7 (n)                                                                 "          164                               7    C.sub.3 H.sub.7 (n)                                                                 CH.sub.3                                                                            H 119    C.sub.3 H.sub.7 (n)                                                                 CH.sub.3                                                                            "          153                               8    C.sub.3 H.sub.7 (n)                                                                 C.sub.2 H.sub.5                                                                     H 107    C.sub.3 H.sub.7 (n)                                                                 C.sub.2 H.sub.5                                                                     "          144                               9    C.sub.3 H.sub.7 (n)                                                                 C.sub.3 H.sub.7 (n)                                                                 H 133    C.sub.3 H.sub.7 (n)                                                                 C.sub.3 H.sub.7 (n)                                                                 "          132                               10   C.sub.4 H.sub.9 (n)                                                                 CH.sub.3                                                                            H 118    C.sub.4 H.sub.9 (n)                                                                 CH.sub.3                                                                            "          143                               11   C.sub.4 H.sub.9 (n)                                                                 C.sub.2 H.sub.5                                                                     H 111    C.sub.4 H.sub.9 (n)                                                                 C.sub.2 H.sub.5                                                                     "          152                               12   C.sub.4 H.sub.9 (n)                                                                 C.sub.3 H.sub.7 (n)                                                                 H 121    C.sub.4 H.sub.9 (n)                                                                 C.sub.3 H.sub.7 (n)                                                                 "          136                               __________________________________________________________________________

EXAMPLE 13 ##STR29##

22.4 g (0.1 mol) of 2-amino-5-propylthio-acetanilide of melting point 98° C. are boiled, together with 20.6 g (0.1 mol) of N,N'-bis-methoxycarbonylisothiourea S-methyl ether and 2.6 g (0.015 mol) of p-toluenesulphonic acid, in 200 ml of absolute methanol for 3 hours, whilst stirring and under reflux. The mixture is then filtered hot and, after cooling, the N-(2-acetamido-4-propylthio-phenyl)-N',N"-bis-methoxycarbonyl-guanidine which has crystallised out is filtered off, rinsed with ether and dried under a high vaccum, melting point 149° C., yield 22 g=58% of theory. The yield can be further increased by working up the mother liquors.

EXAMPLES 14 to 99

The following compounds are obtained from N,N'-disubstituted isothiourea S-methyl ethers and 2-amino-5-substituted acylanilides by the method described in Example 13:

    __________________________________________________________________________             Starting materials                                                              ##STR30##                                                                                                 Melting                                    Example No.                                                                            R             R.sup.5       point (°C.)                         __________________________________________________________________________     14      C.sub.3 H.sub.7                                                                              C.sub.2 H.sub.5                                                                              106                                        15      C.sub.3 H.sub.7                                                                              C.sub.3 H.sub.7                                                                              118                                        16      C.sub.3 H.sub.7                                                                              CH.sub.2 OCH.sub.3                                                                            68                                        17      C.sub.3 H.sub.7                                                                              OCH.sub.3                                                18      C.sub.3 H.sub.7                                                                              H                                                        19      C.sub.3 H.sub.7                                                                              H                                                        20      C.sub.3 H.sub.7                                                                              C.sub.4 H.sub.9                                          21      C.sub.2 H.sub.5                                                                              H                                                        22      C.sub.2 H.sub.5                                                                              C.sub.3 H.sub.7                                          23      C.sub.2 H.sub.5                                                                              CH.sub.2 OCH.sub.3                                       24      C.sub.4 H.sub.9                                                                              H                                                        25      C.sub.4 H.sub.9                                                                              C.sub.3 H.sub.7                                          26      C.sub.4 H.sub.9                                                                              CH.sub.2 OCH.sub.3                                       27      CH.sub.2CHCH.sub.2                                                                           H                                                        28      CH.sub.2CHCH.sub.2                                                                           C.sub.2 H.sub.5                                          29      CH.sub.2 CHCH.sub.2                                                                          C.sub.3 H.sub.7                                          30      HCCCH.sub.2   H                                                        31      HCCCH.sub. 2  C.sub.2 H.sub.5                                          32      HCCCH.sub.2   C.sub.3 H.sub.7                                          33      HCCCH.sub.2   CH.sub.2 OCH.sub.3                                       34      C.sub.4 H.sub.9                                                                              CH.sub.3                                                 35      C.sub.4 H.sub.9                                                                              C.sub.2 H.sub.5                                          36      C.sub.4 H.sub.9                                                                              C.sub.4 H.sub.9                                          37      C.sub.5 H.sub.11                                                                             H                                                        38      C.sub.5 H.sub.11                                                                             CH.sub.3                                                 39      C.sub.5 H.sub.11                                                                             CH.sub.2 OCH.sub.3                                       40      H.sub.3 CHCCHCH.sub.2                                                                        H                                                        41      H.sub.3 CHCCHCH.sub.2                                                                        C.sub.2 H.sub.5                                          42      CH.sub.2C(CH.sub.3)CH.sub.2                                                                  H                                                        43      CH.sub.2C(CH.sub.3)CH.sub.2                                                                  CH.sub.2 OCH.sub.3                                       44      CH.sub.3 OCH.sub.2CH.sub.2                                                                   H                                                        45      CH.sub.3 OCH.sub.2CH.sub.2                                                                   CH.sub.3                                                 46      CH.sub.3 OCH.sub.2CH.sub. 2                                                                  C.sub.2 H.sub.5                                          47      CH.sub.3 OCH.sub.2CH.sub.2                                                                   C.sub.3 H.sub.7                                          48      CH.sub.3 OCH.sub.2CH.sub.2                                                                   CH.sub.2 OCH.sub.3                                       49      CH.sub.3 OCH.sub.2CH.sub.2                                                                   OCH.sub.3                                                50      CH.sub.3 SCH.sub.2CH.sub.2                                                                   H                                                        51      CH.sub.3 SCH.sub.2CH.sub.2                                                                   CH.sub.3                                                 52      CH.sub.3 SCH.sub.2CH.sub.2                                                                   C.sub.2 H.sub.5                                          53      CH.sub.2 SCH.sub.2CH.sub.2                                                                   CH.sub.2OCH.sub.3                                        54      NCCH.sub.2CH.sub.2                                                                           H                                                        55      NCCH.sub.2CH.sub.2                                                                           CH.sub.3                                                 56      NCCH.sub.2CH.sub.2                                                                           C.sub.2 H.sub.5                                          57      NCCH.sub.2CH.sub.2                                                                           CH.sub.2OCH.sub.3                                        58      NCCH.sub.2CH.sub.2CH.sub.2                                                                   H                                                        59      NCCH.sub.2CH.sub.2CH.sub.2                                                                   CH.sub.3                                                 60      NCCH.sub.2CH.sub.2CH.sub.2                                                                   C.sub.2 H.sub.5                                          61      NCCH.sub.2CH.sub.2CH.sub.2                                                                   C.sub.3 H.sub.7                                          62      NCCH.sub.2CH.sub.2CH.sub.2                                                                   CH.sub.2 OCH.sub.3                                       63      CH.sub.3 OCH.sub.2CH.sub.2CH.sub.2                                                           H                                                        64      CH.sub.3 OCH.sub.2CH.sub.2CH.sub.2                                                           CH.sub.3                                                 65      CH.sub.3 OCH.sub. 2CH.sub.2CH.sub.2                                                          C.sub.2 H.sub.5                                          66      CH.sub.3 OCH.sub.2CH.sub.2CH.sub.2                                                           C.sub.3 H.sub.7                                          67      CH.sub.3 OCH.sub.2CH.sub.2CH.sub.2                                                           CH.sub.2 OCH.sub.3                                       68      ClCHCHCH.sub.2                                                                               H                                                        69      ClCHCHCH.sub.2                                                                               CH.sub.3                                                 70      ClCHCHCH.sub.2                                                                               C.sub.2 H.sub.5                                          71      ClCHCHCH.sub.2                                                                               C.sub.3 H.sub.7                                          72      ClCHCHCH.sub.2                                                                               CH.sub.2 OCH.sub.3                                       73      Cl.sub.2 CCHCH.sub.2                                                                         H                                                        74      Cl.sub.2 CCHCH.sub.2                                                                         CH.sub.3                                                 75      Cl.sub.2 CCHCH.sub.2                                                                         C.sub.2 H.sub.5                                          76      Cl.sub.2 CCHCH.sub.2                                                                         C.sub.2 H.sub.7                                          77      Cl.sub.2 CCHCH.sub.2                                                                         CH.sub.2 OCH.sub.3                                       78      ClCHCClCH.sub.2                                                                              H                                                        79      ClCHCClCH.sub.2                                                                              CH.sub.3                                                 80      ClCHCClCH.sub.2                                                                              C.sub.2 H.sub.5                                          81      ClCHCClCH.sub.2                                                                              C.sub.3 H.sub.7                                          82      ClCHCClCH.sub.2                                                                              CH.sub.2 OCH.sub.2                                       83      H.sub.3 CCClCHCH.sub.2                                                                       H                                                        84      H.sub.3 CCClCHCH.sub.2                                                                       CH.sub.3                                                 85      H.sub.3 CCClCHCH.sub.2                                                                       C.sub.2 H.sub.5                                          86      H.sub.3 CCClCHCH.sub. 2                                                                      C.sub.3 H.sub.7                                          87      H.sub.3 CCClCHCH.sub.2                                                                       CH.sub.2 OCH.sub.3                                       88      FHCCHCH.sub.2 H                                                        89      FHCCHCH.sub.2 CH.sub.3                                                 90      FHCCHCH.sub.2 C.sub.2 H.sub.5                                          91      FHCCHCH.sub.2 C.sub.3 H.sub.7                                          92      FHCCHCH.sub.2 CH.sub.2 OCH.sub.3                                       93      C.sub.3 H.sub.7                                                                              CH.sub.2N(CH.sub.3).sub.2                                94      C.sub.3 H.sub.7                                                                              CH.sub.2N(C.sub.2 H.sub.5).sub.2                         95      C.sub.3 H.sub.7                                                                               ##STR31##                                               96      C.sub.3 H.sub.7                                                                               ##STR32##                                               97      C.sub.3 H.sub.7                                                                               ##STR33##                                               98      C.sub.3 H.sub.7                                                                               ##STR34##    117                                        99      C.sub.3 H.sub.7                                                                               ##STR35##                                               __________________________________________________________________________            Substances prepared according to the invention                                  ##STR36##                                                                                                   Melting                                   Example No.                                                                           R             R.sup.5      R.sup.4                                                                           point (°C.)                        __________________________________________________________________________     14     C.sub.3 H.sub.7                                                                              C.sub.2 H.sub.3                                                                             CH.sub.3                                                                          148                                       15     C.sub.3 H.sub.7                                                                              C.sub.3 H.sub.7                                                                             CH.sub.3                                                                          153                                       16     C.sub.3 H.sub.7                                                                              CH.sub.2 OCH.sub.3                                                                          CH.sub.3                                                                          120                                       17     C.sub.3 H.sub.7                                                                              OCH.sub.3    CH.sub.3                                     18     C.sub.3 H.sub.7                                                                              H            CH.sub.3                                                                          144                                       19     C.sub.3 H.sub.7                                                                              H            C.sub.2 H.sub.3                              20     C.sub.3 H.sub.7                                                                              C.sub.4 H.sub.9                                                                             CH.sub.3                                                                          139                                       21     C.sub.2 H.sub.3                                                                              H            CH.sub.3                                     22     C.sub.2 H.sub.5                                                                              C.sub.3 H.sub.7                                                                             CH.sub.3                                     23     C.sub.2 H.sub.5                                                                              CH.sub.2 OCH.sub.3                                                                          CH.sub.3                                     24     C.sub.4 H.sub.9                                                                              H            CH.sub.3                                                                          144                                       25     C.sub.4 H.sub.9                                                                              C.sub.3 H.sub.7                                                                             CH.sub.3                                                                          134                                       26     C.sub.4 H.sub.9                                                                              CH.sub.2 OCH.sub.3                                                                          CH.sub.3                                                                          111                                       27     CH.sub.2CHCH.sub.2                                                                           H            CH.sub.3                                     28     CH.sub.2CHCH.sub.2 C.sub.2 H.sub.3                                                                        CH.sub.3                                     29     CH.sub.2CHCH.sub.2 C.sub.3 H.sub.7                                                                        CH.sub.3                                     30     HCC CH.sub.2  H            CH.sub.3                                     31     HCCCH.sub.2   C.sub.2 H.sub.3                                                                             CH.sub.3                                     32     HCCCH.sub.2   C.sub.3 H.sub.7                                                                             CH.sub.3                                     33     HCCCH.sub.2   CH.sub.2 OCH.sub.3                                                                          CH.sub.3                                     34     C.sub.4 H.sub.9                                                                              CH.sub.3     CH.sub.3                                                                          137                                       35     C.sub.4 H.sub.9                                                                              C.sub.2 H.sub.5                                                                             CH.sub.3                                                                          126                                       36     C.sub.4 H.sub.9                                                                              C.sub.4 H.sub.9                                                                             CH.sub.3                                                                          104                                       37     C.sub.5 H.sub.11                                                                             H            CH.sub.3                                                                          130                                       38     C.sub.5 H.sub.11                                                                             CH.sub.3     CH.sub.3                                                                          128                                       39     C.sub.5 H.sub.11                                                                             CH.sub.2 OCH.sub.3                                                                          CH.sub.3                                                                           86                                       40     CH.sub.3CHCHCH.sub.2                                                                         H            CH.sub.3                                     41     CH.sub.3CHCHCH.sub.2       CH.sub.3                                     42     CH.sub.2C(CH.sub.3)C.sub.2 H.sub.5                                                           CH.sub.3                                                  43     CH.sub.2C(CH.sub.3)CH.sub.2 OCH.sub.3                                                        CH.sub.3                                                  44     CH.sub.3OCH.sub.2CH.sub.2                                                                    H            CH.sub.3                                     45     CH.sub.3OCH.sub.2CH.sub.2                                                                    CH.sub. 3    CH.sub.3                                     46     CH.sub.3OCH.sub.2CH.sub.2                                                                    C.sub.2 H.sub.5                                                                             CH.sub.3                                     47     CH.sub.3OCH.sub.2CH.sub.2                                                                    C.sub.3 H.sub.7                                                                             CH.sub.3                                     48     CH.sub.3OCH.sub.2CH.sub.2                                                                    CH.sub.2 OCH.sub.3                                                                          CH.sub.3                                     49     CH.sub.3OCH.sub.2CH.sub.2                                                                    OCH.sub.3    CH.sub.3                                     50     CH.sub.3 SCH.sub.2CH.sub.2                                                                   H            CH.sub.3                                     51     CH.sub.3 SCH.sub.2CH.sub.2                                                                   CH.sub.3     CH.sub.3                                     52     CH.sub.3 SCH.sub.2CH.sub.2                                                                   C.sub.2 H.sub.5                                                                             CH.sub.3                                     53     CH.sub.3 SCH.sub.2CH.sub.2                                                                   CH.sub.2OCH.sub.3                                                                           CH.sub.3                                     54     NCCH.sub.2CH.sub.2                                                                           H            CH.sub.3                                     55     NCCH.sub.2CH.sub.2                                                                           CH.sub.3     CH.sub.3                                     56     NCCH.sub.2CH.sub.2                                                                           C.sub.2 H.sub.5                                                                             CH.sub.3                                     57     NCCH.sub.2CH.sub.2                                                                           CH.sub.2OCH.sub.3                                                                           CH.sub.3                                     58     NCCH.sub.2CH.sub.2CH.sub.2                                                                   H            CH.sub.3                                     59     NCCH.sub.2CH.sub.2CH.sub.2                                                                   CH.sub.3     CH.sub.3                                     60     NCCH.sub.2CH.sub.2CH.sub.2                                                                   C.sub.2 H.sub.5                                                                             CH.sub.3                                     61     NCCH.sub.2CH.sub.2CH.sub.2                                                                   C.sub.3 H.sub.7                                                                             CH.sub.3                                     62     NC CH.sub.2CH.sub.2CH.sub.2                                                                  CH.sub.2 OCH.sub.3                                                                          CH.sub.3                                     63     CH.sub.3CH.sub.2CH.sub.2CH.sub.2                                                             H            CH.sub.3                                     64     CH.sub.3 OCH.sub.2CH.sub.2CH.sub.2                                                           CH.sub.3     CH.sub.3                                     65     CH.sub.3 OCH.sub.2CH.sub.2CH.sub.2                                                           C.sub.2 H.sub.5                                                                             CH.sub.3                                     66     CH.sub.3 OCH.sub.2CH.sub.2CH.sub.2                                                           C.sub.3 H.sub.7                                                                             CH.sub.3                                     67     CH.sub.3 OCH.sub.2CH.sub.2CH.sub.2                                                           CH.sub.2 OCH.sub.3                                                                          CH.sub.3                                     68     ClCHCHCH.sub.2                                                                               H            CH.sub.3                                     69     ClCHCHCH.sub.2                                                                               CH.sub.3     CH.sub.3                                     70     ClCHCHCH.sub.2                                                                               C.sub.2 H.sub.5                                                                             CH.sub.3                                     71     ClCHCHCH.sub.2                                                                               C.sub.3 H.sub.7                                                                             CH.sub.3                                     72     ClCHCHCH.sub.2                                                                               CH.sub.2 OCH.sub.3                                                                          CH.sub.3                                     73     Cl.sub.2 CCHCH.sub.2                                                                         H            CH.sub.3                                     74     Cl.sub.2 CCHCH.sub.2                                                                         CH.sub.3     CH.sub.3                                     75     Cl.sub.2 CCHCH.sub.2                                                                         C.sub.2 H.sub.3                                                                             CH.sub.3                                     76     Cl.sub.2 CCHCH.sub.2                                                                         C.sub.3 H.sub.7                                                                             CH.sub.3                                     77     Cl.sub.2 CCHCH.sub.2                                                                         CH.sub.2 OCH.sub.3                                                                          CH.sub.3                                     78     ClCHCClCH.sub.2                                                                              H            CH.sub.3                                     79     ClCHCClCH.sub.2                                                                              CH.sub.3     CH.sub.3                                     80     ClCHCClCH.sub.2                                                                              C.sub.2 H.sub.3                                                                             CH.sub.3                                     81     ClCHCClCH.sub.2                                                                              C.sub.3 H.sub.7                                                                             CH.sub.3                                     82     ClCHCClCH.sub.2                                                                              CH.sub.2 OCH.sub.3                                                                          CH.sub.3                                     83     H.sub.3 CCClCHCH.sub.2                                                                       H            CH.sub.3                                     84     H.sub.3 CCClCHCH.sub.2                                                                       CH.sub.2     CH.sub.3                                     85     H.sub.3 CCClCHCH.sub.2                                                                       C.sub.2 H.sub.3                                                                             CH.sub.3                                     86     H.sub.3 CCClCHCH.sub.2                                                                       C.sub.3 H.sub.7                                                                             CH.sub.3                                     87     H.sub.3 CCClCH.sub.2                                                                         CH.sub.2 OCH.sub.3                                                                          CH.sub.3                                     88     FHCCHCH.sub.2 H            CH.sub.3                                     89     FHCCHCH.sub.2 CH.sub.3     CH.sub.3                                     90     FHCCHCH.sub.2 C.sub.2 H.sub.3                                                                             CH.sub.3                                     91     FHCCHCH.sub.2 C.sub.3 H.sub.7                                                                             CH.sub.3                                     92     FHCCHCH.sub.2 CH.sub.2 OCH.sub.3                                                                          CH.sub.3                                     93     C.sub.3 H.sub.7                                                                              CH.sub.2N(CH.sub.3).sub.2                                                                   CH.sub.3                                     94     C.sub.3 H.sub.7                                                                              CH.sub.2N(C.sub.2 H.sub.5).sub.2                                                            CH.sub.3                                     95     C.sub.3 H.sub.7                                                                               ##STR37##   CH.sub.3                                     96     C.sub.3 H.sub.7                                                                               ##STR38##   CH.sub.3                                     97     C.sub.3 H.sub.7                                                                               ##STR39##   CH.sub.3                                     98     C.sub.3 H.sub.7                                                                               ##STR40##   CH.sub.3                                                                          130                                       99     C.sub.3 H.sub.7                                                                               ##STR41##                                                __________________________________________________________________________

EXAMPLE 100 ##STR42##

18.3 g (0.0815 mol) of 2-amino-4-propylthio-acetanilide are stirred, in 350 ml of methanol and 9.5 ml of glacial acetic acid, with 18.1 g (0.088 mol) of N,N'-bis-methoxycarbonyl-isothiourea S-methyl ether for 15 hours at room temperature. After cooling, the precipitate is filtered off, washed with ether and recrystallised from ethyl acetate. This gives 17 g of N-(2-acetylamino-5-propylthiophenyl)-N'-N"-bis-methoxycarbonyl-guanidine of melting point 138° C.

The 2-amino-4-propylthio-acetanilide (melting point 105° C.) used as the starting material is obtained by catalytic hydrogenation of 2-nitro-4-propylthio-acetanilide, melting point 76° C. The 2-Nitro-4-propylthio-acetanilide, is prepared by reacting 2-nitro-4-thiocyanatoacetanilide with propyl bromide in the presence of NaBH₄ in dimethylformamide as the solvent, or by acetylating 2-nitro-4-propylthio-aniline, melting point 41°-42° C., with acetic anhydride or acetyl chloride.

EXAMPLES 101 TO 184

The following compounds are obtained from N,N'-disubstituted isothiourea S-methyl ethers and 2-amino-4-substituted acylanilides by the method described in Example 13:

    __________________________________________________________________________     Starting materials             Substances prepared according to the                                           invention                                        ##STR43##                                                                                                     ##STR44##                                      Ex.                      Melting                         Melting               No.                                                                               R            R.sup.5  point (°C.)                                                                   R             R.sup.5  R.sup.4                                                                           point                                                                          (°C.)          __________________________________________________________________________     101                                                                               C.sub.3 H.sub.7                                                                             C.sub.2 H.sub.5                                                                         107   C.sub.3 H.sub.7                                                                              C.sub.2 H.sub.5                                                                         CH.sub.3                                                                          130                   102                                                                               C.sub.3 H.sub.7                                                                             C.sub.3 H.sub.7                                                                         111   C.sub.3 H.sub.7                                                                              C.sub.3 H.sub.7                                                                         CH.sub.3                                                                          126                   103                                                                               C.sub.3 H.sub.7                                                                             CH.sub.2 OCH.sub.3                                                                      54-55 C.sub.3 H.sub.7                                                                              CH.sub.2 OCH.sub.3                                                                      CH.sub.3                                                                          115-116               104                                                                               C.sub.3 H.sub.7                                                                             OCH.sub.3      C.sub.3 H.sub.7                                                                              OCH.sub.3                                                                               CH.sub.3                 105                                                                               C.sub.3 H.sub.7                                                                             H        111-112                                                                              C.sub.3 H.sub.7                                                                              H        CH.sub.3                                                                          128-130               106                                                                               C.sub.3 H.sub. 7                                                                            H              C.sub.3 H.sub.7                                                                              H        C.sub.2 H.sub.5          107                                                                               C.sub.3 H.sub.7                                                                             C.sub.4 H.sub.9                                                                         108-109                                                                              C.sub.3 H.sub.7                                                                              C.sub.4 H.sub.9                                                                         CH.sub.3                                                                          116-117               108                                                                               C.sub.2 H.sub.5                                                                             H              C.sub.2 H.sub.5                                                                              H        CH.sub.3                 109                                                                               C.sub.2 H.sub.5                                                                             C.sub.3 H.sub.7                                                                               C.sub.2 H.sub.5                                                                              C.sub.3 H.sub.7                                                                         CH.sub.3                 110                                                                               C.sub.2 H.sub.5                                                                             CH.sub.2 OCH.sub.3                                                                            C.sub.2 H.sub.5                                                                              CH.sub.2 OCH.sub.3                                                                      CH.sub.3                 111                                                                               C.sub.4 H.sub.9                                                                             H        117-118                                                                              C.sub.4 H.sub.9                                                                              H        CH.sub.3                                                                          139                   112                                                                               C.sub.4 H.sub.9                                                                             C.sub.3 H.sub.7                                                                               C.sub.4 H.sub.9                                                                              C.sub.3 H.sub.7                                                                         CH.sub.3                 113                                                                               C.sub.4 H.sub.9                                                                             CH.sub.2 OCH.sub.3                                                                            C.sub.4 H.sub.9                                                                              CH.sub.2 OCH.sub.3                                                                      CH.sub.3                 114                                                                               CH.sub.2CHCH.sub.2                                                                          H              CH.sub.2CHCH.sub.2                                                                           H        CH.sub.3                 115                                                                               CH.sub.2CHCH.sub.2                                                                          C.sub.2 H.sub.5                                                                               CH.sub.2CHCH.sub.2                                                                           C.sub.2 H.sub.5                                                                         CH.sub.3                 116                                                                               CH.sub.2CHCH.sub.2                                                                          C.sub.3 H.sub.7                                                                               CH.sub.2CHCH.sub.2                                                                           C.sub.3 H.sub.7                                                                         CH.sub.3                 117                                                                               HCCCH.sub.2  H              HCCCH.sub.2   H        CH.sub.3                 118                                                                               HCCCH.sub.2  C.sub.2 H.sub.5                                                                               HCCCH.sub.2   C.sub.2 H.sub.5                                                                         CH.sub.3                 119                                                                               HCCCH.sub.2  C.sub.3 H.sub.7                                                                               HCCCH.sub.2   C.sub.3 H.sub.7                                                                         CH.sub.3                 120                                                                               HCCCH.sub.2  CH.sub.2 OCH.sub.3                                                                            HCCCH.sub.2   CH.sub.2 OCH.sub.3                                                                      CH.sub.3                 121                                                                               C.sub.4 H.sub.9                                                                             C.sub.2 H.sub.5                                                                         109   C.sub.4 H.sub.9                                                                              C.sub.2 H.sub.5                                                                         CH.sub.3                                                                          120                   122                                                                               C.sub.4 H.sub.9                                                                             CH.sub.3 114   C.sub.4 H.sub.9                                                                              CH.sub.3 CH.sub.3                                                                          144                   123                                                                               H.sub.3 CHCCHCH.sub.2                                                                       H              CH.sub.3CHCHCH.sub.2                                                                         H        CH.sub.3                 124                                                                               H.sub.3 CHCCHCH.sub.2                                                                       C.sub.2 H.sub.5                                                                               CH.sub.3CHCHCH.sub.2 C.sub.2 H.sub.5                                                                  CH.sub.3                 125                                                                               CH.sub.2C(CH.sub.3)CH.sub.2                                                                 H              CH.sub.2C(CH.sub.3)CH.sub.2                                                                  H        CH.sub.3                 126                                                                               CH.sub.2C(CH.sub.3)                                                                         CH.sub.2 OCH.sub.3                                                                            CH.sub.2C(CH.sub.3)CH.sub.2 CH.sub.2                                                         OCH.sub.3                                                                               CH.sub.3                 127                                                                               CH.sub.3 OCH.sub.2CH.sub.2                                                                  H              CH.sub.3OCH.sub.2CH.sub.2                                                                    H        CH.sub.3                 128                                                                               CH.sub.3 OCH.sub.2CH.sub.2                                                                  CH.sub.3       CH.sub.3OCH.sub.2CH.sub.2                                                                    CH.sub.3 CH.sub.3                                                                          127-128               129                                                                               CH.sub.3 OCH.sub.2CH.sub.2                                                                  C.sub.2 H.sub.5                                                                               CH.sub.3OCH.sub.2CH.sub.2                                                                    C.sub.2 H.sub.5                                                                         CH.sub.3                 130                                                                               CH.sub.3 OCH.sub.2CH.sub.2                                                                  C.sub.3 H.sub.7                                                                               CH.sub.3OCH.sub.2CH.sub.2                                                                    C.sub.3 H.sub.7                                                                         CH.sub.3                                                                          104-105               131                                                                               CH.sub.3 OCH.sub.2CH.sub.2                                                                  CH.sub.2 OCH.sub.3                                                                            CH.sub.3OCH.sub.2CH.sub.2                                                                    CH.sub.2 OCH.sub.3                                                                      CH.sub.3                 132                                                                               CH.sub.3 O CH.sub.2CH.sub.2                                                                 OCH.sub.3      CH.sub.3OCH.sub.2CH.sub.2                                                                    OCH.sub.3                                                                               CH.sub.3                 133                                                                               CH.sub.3 SCH.sub.2CH.sub.2                                                                  H              CH.sub.3 SCH.sub.2CH.sub.2                                                                   H        CH.sub.3                 134                                                                               CH.sub.3 SCH.sub.2CH.sub.2                                                                  CH.sub.3       CH.sub.3 SCH.sub.2CH.sub.2                                                                   CH.sub.3 CH.sub.3                 135                                                                               CH.sub.3 SCH.sub.2CH.sub.2                                                                  C.sub.2 H.sub.5                                                                               CH.sub.3 SCH.sub.2CH.sub.2                                                                   C.sub.2 H.sub.5                                                                         CH.sub.3                 136                                                                               CH.sub.3 SCH.sub.2CH.sub.2                                                                  CH.sub.2OCH.sub.3                                                                             CH.sub.3 SCH.sub.2CH.sub.2                                                                   CH.sub.2OCH.sub.3                                                                       CH.sub.3                 137                                                                               NCCH.sub.2CH.sub.2                                                                          H              NCCH.sub.2CH.sub.2                                                                           H        CH.sub.3                 138                                                                               NCCH.sub.2CH.sub.2                                                                          CH.sub.3       NCCH.sub.2CH.sub.2                                                                           CH.sub.3 CH.sub.3                 139                                                                               NCCH.sub.2CH.sub.2                                                                          C.sub.2 H.sub.5                                                                         60-63 NCCH.sub.2CH.sub.2                                                                           C.sub.2 H.sub.5                                                                         CH.sub.3                                                                          181                                            (decom-                                                                        position)                                             140                                                                               NCCH.sub.2CH.sub.2                                                                          CH.sub.2OCH.sub.3                                                                             NCCH.sub.2CH.sub.2                                                                           CH.sub.2OCH.sub.3                                                                       CH.sub.3                 141                                                                               NCCH.sub.2CH.sub.2CH.sub.2                                                                  H              NCCH.sub.2CH.sub.2CH.sub.2                                                                   H        CH.sub.3                 142                                                                               NCCH.sub.2CH.sub.2CH.sub.2                                                                  CH.sub.3       NCCH.sub.2CH.sub.2CH.sub.2                                                                   CH.sub.3 CH.sub.3                 143                                                                               NCCH.sub.2CH.sub.2CH.sub.2                                                                  C.sub.2 H.sub.5                                                                               NCCH.sub.2CH.sub.2CH.sub.2                                                                   C.sub.2 H.sub.5                                                                         CH.sub.3                 144                                                                               NCCH.sub.2CH.sub.2CH.sub.2                                                                  C.sub.3 H.sub.7                                                                               NCCH.sub.2CH.sub.2CH.sub.2                                                                   C.sub.3 H.sub.7                                                                         CH.sub.3                 145                                                                               NCCH.sub.2CH.sub.2CH.sub.2                                                                  CH.sub.2 OCH.sub.3                                                                            NCCH.sub.2CH.sub.2CH.sub.2                                                                   CH.sub.2 OCH.sub.3                                                                      CH.sub.3                 146                                                                               CH.sub.3 OCH.sub.2CH.sub.2CH.sub.2                                                          H              CH.sub.3 OCH.sub.2CH.sub.2CH.sub.2                                                           H        CH.sub.3                 147                                                                               CH.sub.3 OCH.sub.2CH.sub.2CH.sub.2                                                          CH.sub.3       CH.sub.3 OCH.sub.2CH.sub.2CH.sub.2                                                           CH.sub.3 CH.sub.3                 148                                                                               CH.sub.3 OCH.sub.2CH.sub.2CH.sub.2                                                          C.sub.2 H.sub.5                                                                               CH.sub.3 OCH.sub.2CH.sub.2CH.sub.2                                                           C.sub.2 H.sub.5                                                                         CH.sub.3                 149                                                                               CH.sub.3 OCH.sub.2CH.sub.2CH.sub.2                                                          C.sub.3 H.sub.7                                                                               CH.sub.3 OCH.sub.2CH.sub.2CH.sub.2                                                           C.sub.3 H.sub.7                                                                         CH.sub.3                 150                                                                               CH.sub.3 OCH.sub.2CH.sub.2CH.sub.2                                                          CH.sub.2 OCH.sub.3                                                                            CH.sub.3 OCH.sub.2CH.sub.2CH.sub.2                                                           CH.sub.2 OCH.sub.3                                                                      CH.sub.3                 151                                                                               ClCHCHCH.sub.2                                                                              H              ClCHCHCH.sub.2                                                                               H        CH.sub.3                 152                                                                               ClCHCHCH.sub.2                                                                              CH.sub.3       ClCHCHCH.sub.2                                                                               CH.sub.3 CH.sub.3                 153                                                                               ClCHCHCH.sub.2                                                                              C.sub.2 H.sub.5                                                                               ClCHCHCH.sub.2                                                                               C.sub.2 H.sub.5                                                                         CH.sub.3                 154                                                                               ClCHCHCH.sub.2                                                                              C.sub.3 H.sub.7                                                                               ClCHCHCH.sub.2                                                                               C.sub.3 H.sub.7                                                                         CH.sub.3                 155                                                                               ClCH.sub.2CH.sub.2CH.sub.2                                                                  CH.sub.3 130-132                                                                              ClCH.sub.2CH.sub.2CH.sub.2                                                                   CH.sub.3 CH.sub.3                                                                          127-128               156                                                                               ClCH.sub.2CH.sub.2CH.sub.2                                                                  C.sub.2 H.sub.5                                                                         90-92 ClCH.sub.2CH.sub.2CH.sub.2                                                                   C.sub.2 H.sub.5                                                                         CH.sub.3                                                                          134                   157                                                                               ClCH.sub.2CH.sub.2CH.sub.2                                                                  C.sub.3 H.sub.7                                                                         71-73 ClCH.sub.2CH.sub.2CH.sub.2                                                                   C.sub.3 H.sub.                                                                          CH.sub.3                                                                          135                   158                                                                               ClCH.sub.2CH.sub.2CH.sub.2                                                                  H        74-75 ClCH.sub.2CH.sub.2CH.sub.2                                                                   H        CH.sub.3                                                                          126                   159                                                                               ClCHCHCH.sub.2                                                                              CH.sub.2 OCH.sub.3                                                                            ClCHCHCH.sub.2                                                                               CH.sub.2 OCH.sub.3                                                                      CH.sub.3                 160                                                                               Cl.sub.2 CCHCH.sub.2                                                                        H              Cl.sub.2 CCHCH.sub.2                                                                         H        CH.sub.3                 161                                                                               Cl.sub.2 CCHCH.sub.2                                                                        CH.sub.3       Cl.sub.2 CCHCH.sub.2                                                                         CH.sub.3 CH.sub.3                 162                                                                               Cl.sub.2 CCHCH.sub.2                                                                        C.sub.2 H.sub.5                                                                               Cl.sub.2 CCHCH.sub.2                                                                         C.sub.2 H.sub.5                                                                         CH.sub.3                 163                                                                               Cl.sub.2 CCHCH.sub.2                                                                        C.sub.3 H.sub.7                                                                               Cl.sub.2 CCHCH.sub.2                                                                         C.sub.3 H.sub.7                                                                         CH.sub.3                 164                                                                               Cl.sub.2 CCHCH.sub.2                                                                        CH.sub.2 OCH.sub.3                                                                            Cl.sub.2 CCHCH.sub.2                                                                         CH.sub.2 OCH.sub.3                                                                      CH.sub.3                 165                                                                               ClCHCClCH.sub.2                                                                             H              ClCHCClCH.sub.2                                                                              H        CH.sub.3                 166                                                                               ClCHCClCH.sub.2                                                                             CH.sub.3       ClCHCClCH.sub.2                                                                              CH.sub.3 CH.sub.3                 167                                                                               ClCHCClCH.sub.2                                                                             C.sub.2 H.sub.5                                                                               ClCHCClCH.sub.2                                                                              C.sub.2 H.sub.5                                                                         CH.sub.3                 168                                                                               ClCHCClCH.sub.2                                                                             C.sub.3 H.sub.7                                                                               ClCHCClCH.sub.2                                                                              C.sub.3 H.sub.7                                                                         CH.sub.3                 169                                                                               ClCHCClCH.sub.2                                                                             CH.sub.2 OCH.sub.3                                                                            ClCHCClCH.sub.2                                                                              CH.sub.2 OCH.sub.3                                                                      CH.sub.3                 170                                                                               H.sub.3 CCClCHCH.sub.2                                                                      H              H.sub.3 CCClCHCH.sub.2                                                                       H        CH.sub.3                 171                                                                               H.sub.3 CCClCHCH.sub.2                                                                      CH.sub.3       H.sub.3 CCClCHCH.sub.2                                                                       CH.sub.3 CH.sub.3                 172                                                                               H.sub.3 CCClCHCH.sub.2                                                                      C.sub.2 H.sub.5                                                                               H.sub.3 CCClCHCH.sub.2                                                                       C.sub.2 H.sub.5                                                                         CH.sub.3                 173                                                                               H.sub.3 CCClCHCH.sub.2                                                                      C.sub.3 H.sub.7                                                                               H.sub.3 CCClCHCH.sub.2                                                                       C.sub.3 H.sub.7                                                                         CH.sub.3                 174                                                                               H.sub.3 CCClCHCH.sub.2                                                                      CH.sub.2 OCH.sub.3                                                                            H.sub.3 CCClCHCH.sub.2                                                                       CH.sub.2 OCH.sub.3                                                                      CH.sub.3                 175                                                                               FHCCHCH.sub.2                                                                               H              FHCCHCH.sub.2 H        CH.sub.3                 176                                                                               FHCCHCH.sub.2                                                                               CH.sub.3       FHCCHCH.sub.2 CH.sub.3 CH.sub.3                 177                                                                               FHCCHCH.sub.2                                                                               C.sub.2 H.sub.5                                                                               FHCCH CH.sub.2                                                                               C.sub.2 H.sub.5                                                                         CH.sub.3                 178                                                                               FHCCHCH.sub.2                                                                               C.sub.3 H.sub.7                                                                               FHCCHCH.sub.2 C.sub.3 H.sub.7                                                                         CH.sub.3                 179                                                                               FHCCHCH.sub.2                                                                               CH.sub.2 OCH.sub.3                                                                            FHCCHCH.sub.2 CH.sub.2 OCH.sub.3                                                                      CH.sub.3                 180                                                                               C.sub.3 H.sub.7                                                                             CH.sub.2N(CH.sub.3).sub.2                                                                     C.sub.3 H.sub.7                                                                              CH.sub.2N(CH.sub.3).sub.2                                                               CH.sub.3                 181                                                                               C.sub.3 H.sub.7                                                                             CH.sub.2N(C.sub.2 H.sub.5).sub.2                                                              C.sub.3 H.sub.7                                                                              CH.sub.2N(C.sub.2 H.sub.5).su                                                  b.2      CH.sub.3                 182                                                                               C.sub.3 H.sub.7                                                                              ##STR45##     C.sub.3 H.sub.7                                                                               ##STR46##                                                                              CH.sub.3                 183                                                                               C.sub.3 H.sub.7                                                                              ##STR47##     C.sub.3 H.sub.7                                                                               ##STR48##                                                                              CH.sub.3                                                                          97-98                 184                                                                               C.sub.3 H.sub.7                                                                              ##STR49##     C.sub.3 H.sub.7                                                                               ##STR50##                                                                              CH.sub.3                 __________________________________________________________________________

EXAMPLE 185 ##STR51##

19.8 g of N-(2-proplonylamino-5-propylthio-phenyl)-N'-N"-bis-methoxycarbonyl-guanidine (Example 5) are dissolved in 650 ml of acetic anhydride. 42 g of hydrogen peroxide (30% strength) are added and the mixture is stirred overnight and evaporated in vacuo.

The residue crystallises (after triturating with a mixture of ethyl acetate and ether). The precipitate is filtered off and recrystallised and ethyl acetate. Yield: 22.2 g, Fp 165°-166° C. u. Z.

EXAMPLES 186 TO 228

In each of the Examples a sulphone of the following general formula is obtained by oxidising the corresponding thioether in an analogous procedure to Example 185.

    ______________________________________                                          ##STR52##                                                                     Example                                                                        No.      R                  R.sup.5                                            ______________________________________                                         186      C.sub.3 H.sub.7    H                                                  187      C.sub.3 H.sub.7    CH.sub.3                                           188      C.sub.3 H.sub.7    C.sub.3 H.sub.7                                    189      C.sub.3 H.sub.7    C.sub.4 H.sub.9                                    190      C.sub.3 H.sub.7    C.sub.5 H.sub.11                                   191      C.sub.3 H.sub.7    CH.sub.2 OCH.sub.3                                 192      C.sub.3 H.sub.7                                                                                    ##STR53##                                         193      C.sub.4 H.sub.9    H                                                  194      C.sub.4 H.sub.9    CH.sub.3                                           195      C.sub.4 H.sub.9    C.sub.2 H.sub.5                                    196      C.sub.4 H.sub.9    C.sub.3 H.sub.7                                    197      C.sub.4 H.sub.9    C.sub.4 H.sub.9                                    198      C.sub.4 H.sub.9    CH.sub.2 OCH.sub.3                                 199      ClCHCHCH.sub.2     H                                                  200      ClCHCHCH.sub.2     CH.sub.3                                           201      ClCHCHCH.sub.2     C.sub.2 H.sub.5                                    202      ClCHCHCH.sub.2     C.sub.3 H.sub.7                                    203      ClCHCHCH.sub.2     C.sub.4 H.sub.9                                    204      ClCHCHCH.sub.2     CH.sub.2 OCH.sub.3                                 205      NCCH.sub.2 CH.sub.2                                                                               H                                                  206      NCCH.sub.2 CH.sub.2                                                                               CH.sub.3                                           207      NCCH.sub.2 CH.sub.2                                                                               C.sub.2 H.sub.5                                    208      NCCH.sub.2 CH.sub.2                                                                               C.sub.3 H.sub.7                                    209      NCCH.sub.2 CH.sub.2                                                                               C.sub.4 H.sub.9                                    210      NCCH.sub.2 CH.sub.2                                                                               CH.sub.2 OCH.sub.3                                 211      NCCH.sub.2 CH.sub.2CH.sub.2                                                                       H                                                  212      NCCH.sub.2 CH.sub.2CH.sub.2                                                                       CH.sub.3                                           213      NCCH.sub.2 CH.sub.2CH.sub.2                                                                       C.sub.2 H.sub.5                                    214      NCCH.sub.2 CH.sub.2CH.sub.2                                                                       C.sub.3 H.sub.7                                    215      NCCH.sub.2 CH.sub.2CH.sub.2                                                                       C.sub.4 H.sub.9                                    216      NCCH.sub.2 CH.sub.2CH.sub.2                                                                       CH.sub.2 OCH.sub.3                                 217      H.sub.3 COCH.sub.2 CH.sub.2                                                                       H                                                  218      H.sub.3 COCH.sub.2 CH.sub.2                                                                       CH.sub.3                                           219      H.sub.3 COCH.sub.2 CH.sub.2                                                                       C.sub.2 H.sub.5                                    220      H.sub.3 COCH.sub.2 CH.sub.2                                                                       C.sub.3 H.sub.7                                    221      H.sub.3 COCH.sub.2 CH.sub.2                                                                       C.sub.4 H.sub.9                                    222      H.sub. 3 COCH.sub.2 CH.sub.2                                                                      CH.sub.2 OCH.sub.3                                 223      H.sub.3 COCH.sub.2 CH.sub.2 CH.sub.2                                                              H                                                  224      H.sub.3 COCH.sub.2 CH.sub.2 CH.sub.2                                                              CH.sub.3                                           225      H.sub.3 COCH.sub.2 CH.sub.2 CH.sub.2                                                              C.sub.2 H.sub.5                                    226      H.sub.3 COCH.sub.2 CH.sub.2 CH.sub.2                                                              C.sub.3 H.sub.7                                    227      H.sub.3 COCH.sub.2 CH.sub.2 CH.sub.2                                                              C.sub.4 H.sub.9                                    228      H.sub.3 COCH.sub.2 CH.sub.2 CH.sub.2                                                              CH.sub.2 OCH.sub.3                                 ______________________________________                                    

EXAMPLES 229 TO 272

In each of these examples, a sulphone of the following general formula is obtained by oxidising the corresponding thioether in an analogous procedure to Example 185:

    ______________________________________                                          ##STR54##                                                                     Example                                                                        No.     R                  R.sup.5                                             ______________________________________                                         229     C.sub.3 H.sub.7    H                                                   230     C.sub.3 H.sub.7    CH.sub.3                                            231     C.sub.3 H.sub.7    C.sub.3 H.sub.7                                     232     C.sub.3 H.sub.7    C.sub.4 H.sub.9                                     233     C.sub.3 H.sub.7    C.sub.5 H.sub.11                                    234     C.sub.3 H.sub.7    CH.sub.2 OCH.sub.3                                  235     C.sub.3 H.sub.7                                                                                    ##STR55##                                          236     C.sub.4 H.sub.9    H                                                   237     C.sub.4 H.sub.9    CH.sub.3                                            238     C.sub.4 H.sub.9    C.sub.2 H.sub.5                                     239     C.sub.4 H.sub.9    C.sub.3 H.sub.7                                     240     C.sub.4 H.sub.9    C.sub.4 H.sub.9                                     241     C.sub.4 H.sub.9    CH.sub.2 OCH.sub.3                                  242     ClCHCHCH.sub.2     H                                                   243     ClCHCHCH.sub.2     CH.sub.3                                            244     ClCHCHCH.sub.2     C.sub.2 H.sub.5                                     245     ClCHCHCH.sub.2     C.sub.3 H.sub.7                                     246     ClCHCHCH.sub.2     C.sub.4 H.sub.9                                     247     ClCHCHCH.sub.2     CH.sub.2 OCH.sub. 3                                 248     NCCH.sub.2CH.sub.2 H                                                   249     NCCH.sub.2CH.sub.2 CH.sub.3                                            250     NCCH.sub.2CH.sub.2 C.sub.2 H.sub.5                                     251     NCCH.sub.2CH.sub.2 C.sub.3 H.sub.7                                     252     NCCH.sub.2CH.sub.2 C.sub.4 H.sub.9                                     253     NCCH.sub.2CH.sub.2 CH.sub.2 OCH.sub.4                                  254     NCCH.sub.2CH.sub.2CH.sub.2                                                                        H                                                   255     NCCH.sub.2CH.sub.2CH.sub.2                                                                        CH.sub.3                                            256     NCCH.sub.2CH.sub.2CH.sub.2                                                                        C.sub.2 H.sub.5                                     257     NCCH.sub.2CH.sub.2CH.sub.2                                                                        C.sub.3 H.sub.7                                     258     NCCH.sub.2CH.sub.2CH.sub.2                                                                        C.sub.4 H.sub.9                                     259     NCCH.sub.2CH.sub.2CH.sub.2                                                                        CH.sub.2 OCH.sub.3                                  260     H.sub.3 COCH.sub.2CH.sub.2                                                                        H                                                   261     H.sub.3 COCH.sub.2CH.sub.2                                                                        CH.sub.3                                            262     H.sub.3 COCH.sub.2CH.sub.2                                                                        C.sub.2 H.sub.5                                     263     H.sub.3 COCH.sub.2CH.sub.2                                                                        C.sub.3 H.sub.7                                     264     H.sub.3 COCH.sub.2CH.sub.2                                                                        C.sub.4 H.sub.9                                     265     H.sub.3 COCH.sub.2CH.sub.2                                                                        CH.sub.2 OCH.sub.3                                  266     H.sub.3 COCH.sub.2CH.sub.2CH.sub.2                                                                H                                                   267     H.sub.3 COCH.sub.2CH.sub.2CH.sub.2                                                                CH.sub.3                                            268     H.sub.3 COCH.sub.2CH.sub.2CH.sub.2                                                                C.sub.2 H.sub.5                                     269     H.sub.3 COCH.sub.2CH.sub.2CH.sub.2                                                                C.sub.3 H.sub.7                                     270     H.sub.3 COCH.sub.2CH.sub.2CH.sub.2                                                                C.sub.4 H.sub.9                                     271     H.sub.3 COCH.sub.2CH.sub.2CH.sub.2                                                                CH.sub.2 OCH.sub.3                                  ______________________________________                                    

EXAMPLE 272 ##STR56##

9.9 g of N-(2-propionylamino-propylthio-phenyl)-N,N"-bis-methoxycarbonyl-guanidine (Example 101) are dissolved in 200 ml of acetic anhydride. 25.8 ml of hydrogen peroxide (30% strength) are added, the mixture is stirred for 4 hours at 20° C. and concentrated in vacuo and the residue is recrystallised from ethyl acetate.

Yield: 7.37 g, Fp. 152° C. u. Z.

EXAMPLES 273 TO 315

In each of these Examples, a sulphoxide of the following general formula is obtained by oxidising the corresponding thioether in an analogous procedure to Example 272:

    ______________________________________                                          ##STR57##                                                                     Example                                                                        No.     R                  R.sup.5                                             ______________________________________                                         273     C.sub.3 H.sub.7    H                                                   274     C.sub.3 H.sub.7    CH.sub.3                                            275     C.sub.3 H.sub.7    C.sub.3 H.sub.7                                     276     C.sub.3 H.sub.7    C.sub.4 H.sub.9                                     277     C.sub.3 H.sub.7    C.sub.5 H.sub.11                                    278     C.sub.3 H.sub.7    CH.sub.2 OCH.sub.3                                  279     C.sub.3 H.sub.7                                                                                    ##STR58##                                          280     C.sub.4 H.sub.9    H                                                   281     C.sub.4 H.sub.9    CH.sub.3                                            282     C.sub.4 H.sub.9    C.sub.2 H.sub.5                                     283     C.sub.4 H.sub.9    C.sub.3 H.sub.7                                     284     C.sub.4 H.sub.9    C.sub.4 H.sub.9                                     285     C.sub.4 H.sub.9    CH.sub.2 OCH.sub.3                                  286     ClCHCHCH.sub.2     H                                                   287     ClCHCHCH.sub.2     CH.sub.3                                            288     ClCHCHCH.sub.2     C.sub.2 H.sub.5                                     289     ClCHCHCH.sub.2     C.sub.3 H.sub.7                                     290     ClCHCHCH.sub.2     C.sub.4 H.sub.9                                     291     ClCHCHCH.sub.2     CH.sub.2 OCH.sub.3                                  292     NCCH.sub.2CH.sub.2 H                                                   293     NCCH.sub.2CH.sub.2 CH.sub.3                                            294     NCCH.sub.2CH.sub.2 C.sub.4 H.sub.9                                     295     NCCH.sub.2CH.sub.2 C.sub.3 H.sub.7                                     296     NCCH.sub.2CH.sub.2 C.sub.4 H.sub.9                                     297     NCCH.sub.2CH.sub.2 CH.sub.2 OCH.sub.3                                  298     NCCH.sub.2CH.sub.2CH.sub.2                                                                        H                                                   299     NCCH.sub.2CH.sub.2CH.sub.2                                                                        CH.sub.3                                            300     NCCH.sub.2CH.sub.2CH.sub.2                                                                        C.sub.2 H.sub.5                                     301     NCCH.sub.2CH.sub.2CH.sub.2                                                                        C.sub.3 H.sub.7                                     302     NCCH.sub.2CH.sub.2CH.sub.2                                                                        C.sub.4 H.sub.9                                     303     NCCH.sub.2CH.sub.2CH.sub.2                                                                        CH.sub.2 OCH.sub.3                                  304     H.sub.3 COCH.sub.2CH.sub.2                                                                        H                                                   305     H.sub.3 COCH.sub.2CH.sub.2                                                                        CH.sub.3                                            306     H.sub.3 COCH.sub.2CH.sub.2                                                                        C.sub.2 H.sub.5                                     307     H.sub.3 COCH.sub.2CH.sub.2                                                                        C.sub.3 H.sub.7                                     308     H.sub.3 COCH.sub.2CH.sub.2                                                                        C.sub.4 H.sub.9                                     309     H.sub.3 COCH.sub.2CH.sub.2                                                                        CH.sub.2 OCH.sub.3                                  310     H.sub.3 COCH.sub.2CH.sub.2CH.sub. 2                                                               H                                                   311     H.sub.3 COCH.sub.2CH.sub.2CH.sub.2                                                                CH.sub.3                                            312     H.sub.3 COCH.sub.2CH.sub.2CH.sub.2                                                                C.sub.2 H.sub.5                                     313     H.sub.3 COCH.sub.2CH.sub.2CH.sub.2                                                                C.sub.3 H.sub.7                                     314     H.sub.3 COCH.sub.2CH.sub.2CH.sub.2                                                                C.sub.4 H.sub.9                                     315     H.sub.3 COCH.sub.2CH.sub.2CH.sub.2                                                                CH.sub.2 OCH.sub.3                                  ______________________________________                                    

EXAMPLES 316 TO 358

In each of these Examples, a compound of the following general formula is obtained by oxidising the corresponding thioether in an analogous procedure to Example 272.

    ______________________________________                                          ##STR59##                                                                     Example                                                                        No.     R                  R.sup.5                                             ______________________________________                                         316     C.sub.3 H.sub.7    H                                                   317     C.sub.3 H.sub.7    CH.sub.3                                            318     C.sub.3 H.sub.7    C.sub.3 H.sub.7                                     319     C.sub.3 H.sub.7    C.sub.4 H.sub.9                                     320     C.sub.3 H.sub.7    C.sub.3 H.sub.11                                    321     C.sub.3 H.sub.7    CH.sub.2 OCH.sub.3                                  322     C.sub.3 H.sub.7                                                                                    ##STR60##                                          323     C.sub.4 H.sub.9    H                                                   324     C.sub.4 H.sub.9    CH.sub.3                                            325     C.sub.4 H.sub.9    C.sub.2 H.sub.5                                     326     C.sub.4 H.sub.9    C.sub.3 H.sub.7                                     327     C.sub.4 H.sub.9    C.sub.4 H.sub.9                                     328     C.sub.4 H.sub.9    CH.sub.2 OCH.sub.3                                  329     ClCHCHCH.sub.2     H                                                   330     ClCHCHCH.sub.2     CH.sub.3                                            331     ClCHCHCH.sub.2     C.sub.2 H.sub.5                                     332     ClCHCHCH.sub.2     C.sub.3 H.sub.7                                     333     ClCHCHCH.sub.2     C.sub.4 H.sub.9                                     334     ClCHCHCH.sub.2     CH.sub. 2 OCH.sub.3                                 335     NCCH.sub.2CH.sub.2 H                                                   336     NCCH.sub.2CH.sub.2 CH.sub.3                                            337     NCCH.sub.2CH.sub.2 C.sub.2 H.sub.5                                     338     NCCH.sub.2CH.sub.2 C.sub.3 H.sub.7                                     339     NCCH.sub.2CH.sub.2 C.sub.4 H.sub.9                                     340     NCCH.sub.2CH.sub.2 CH.sub.2 OCH.sub.3                                  341     NCCH.sub.2CH.sub.2CH.sub.2                                                                        H                                                   342     NCCH.sub.2CH.sub.2CH.sub.2                                                                        CH.sub.3                                            343     NCCH.sub.2CH.sub.2CH.sub.2                                                                        C.sub.2 H.sub.5                                     344     NCCH.sub.2CH.sub.2CH.sub.2                                                                        C.sub.3 H.sub.7                                     345     NCCH.sub.2CH.sub.2CH.sub.2                                                                        C.sub.4 H.sub.9                                     346     NCCH.sub.2CH.sub.2CH.sub.2                                                                        CH.sub.2 OCH.sub.3                                  347     H.sub.3 COCH.sub.2CH.sub.2                                                                        H                                                   348     H.sub.3 COCH.sub.2CH.sub.2                                                                        CH.sub.3                                            349     H.sub.3 COCH.sub.2CH.sub.2                                                                        C.sub.2 H.sub.5                                     350     H.sub.3 COCH.sub.2CH.sub.2                                                                        C.sub.3 H.sub.7                                     351     H.sub.3 COCH.sub.2CH.sub.2                                                                        C.sub.4 H.sub.9                                     352     H.sub.3 COCH.sub.2CH.sub.2                                                                        CH.sub.2 OCH.sub.3                                  353     H.sub.3 COCH.sub.2CH.sub.2 CH.sub.2                                                               H                                                   354     H.sub.3 COCH.sub.2CH.sub.2CH.sub.2                                                                CH.sub.3                                            355     H.sub.3 COCH.sub.2CH.sub.2CH.sub.2                                                                C.sub.2 H.sub.5                                     356     H.sub.3 COCH.sub.2CH.sub.2CH.sub.2                                                                C.sub.3 H.sub.7                                     357     H.sub.3 COCH.sub.2CH.sub.2CH.sub.2                                                                C.sub.4 H.sub.9                                     358     H.sub.3 COCH.sub.2CH.sub.2CH.sub.2                                                                CH.sub.2 OCH.sub.3                                  ______________________________________                                    

EXAMPLES FOR THE MANUFACTURE OF COMPOSITIONS Example C 1

A formulation having the following composition is prepared:

    ______________________________________                                         (A) N-(2-butyramido-4-propylthio-phenyl)-                                      N'-N"-bis-methoxy-carbonyl-guanidine                                                                      50,0%                                               (B) Lecithin               1,5%                                                (C) Polyoxyethylenesorbitantrioleate                                                                      2,0%                                                (D) Polyethyleneglycol-laurylether                                                                        2,0%                                                (stabilizer)                                                                   (E) Mineral Oil            43,5%                                               ______________________________________                                    

This formulation is prepared by mixing the components B to E and adding component A by stirring until a uniform dispersion is completed.

Example C 2

A suspension having the following formulation is prepared:

    ______________________________________                                         (A) The formulation of example C 1                                                                       10 g                                                 (B) Polyoxyethylenesorbitantrioleate                                                                     4 g                                                  (C) Polyethyleneglycol-laurylether                                                                       4 g                                                  (stabilizer)                                                                   (D) Oleum Arachidoni      70 g                                                 ______________________________________                                    

This formulation is prepared by mixing and stirring the components until it is a uniform dispersion is completed.

Example C 3

    ______________________________________                                         A formulation having the following composition is prepared:                    ______________________________________                                         (A) N-(2-butyramido-4-propylthio-phenyl)-                                      N'-N"-bis-methoxy-carbonyl-guanidine                                                                      30%                                                 (B) Polyethylenglycol 6000 40%                                                 (C) (Polyoxy(40)stearate)  30%                                                 ______________________________________                                    

The components Polyethyleneglycol 6000 and Polyoxy(40)stearate are mixed at 50°-60° C. and then component 1 is added by stirring. The formulation is solidified by cooling and ground, without remelting of the polyethylene glycol, to a fine powder.

EXAMPLE C 4

A drenchpowder having the following composition is prepared:

    ______________________________________                                         (A) The formulation of example C 3                                                                       15 g                                                 (B) colloidal silica      6 g                                                  (C) Carboxymethylcellulose                                                                               6 g                                                  ______________________________________                                    

The components are blended together until uniform and then are finely powdered.

EXAMPLE C 5

A suspension having the following formulation is prepared:

    ______________________________________                                         (A) The formulation of example C 3                                                                      7,5 g                                                 (B) citric acid, hydrous 0,43 g                                                (C) sodium citrat        0,67 g                                                (D) carboxymethylcellulose                                                                              1,1 g                                                 (E) colloidal silica     1 g                                                   (F) sorbic acid          0,3 g                                                 (G) purified water       to 100 ml                                             ______________________________________                                    

The sorbic acid, citric acid and sodium citrate are added to 90 ml of water which has been heated to 80° C. The colloidal silica and carboxymethyl cellulose are then added, with stirring, until uniformly dispersed and fully hydrated. The mixture is cooled to 45° C. and the formulation of Example 3 is added, with stirring, until it is uniformly dispersed. The suspension is cooled to room temperature and the balance of the water is added.

EXAMPLE C 6

A formulation having the following composition is prepared:

    ______________________________________                                         (A)    N-(2-Propionamido-4-propylthio-phenyl)-                                        N'-N'-bis-                                                                     methoxycarbonyl-guanidine                                                                              50%                                             (B)    Lecithin                1,5%                                            (C)    Polyoxyethylenesorbitantioleate                                                                        2%                                              (D)    Polyethyleneglycol-laurylether                                                                         2%                                              (E)    Mineral Oil             43,5%                                           ______________________________________                                    

This formulation is prepared by mixing the components 2-5 and adding with stirring the component 12 until a uniform dispersion is completed.

EXAMPLE C 7

A suspension having the following formulation is prepared:

    ______________________________________                                         (A)     The formulation of example C 6                                                                        10 g                                            (B)     Polyoxyethylenesorbitantrioleate                                                                      4 g                                             (C)     Polyethyleneglycol-laurylether                                                                        4 g                                             (D)     Oleum Arachidoni       70 g                                            ______________________________________                                    

This formulation is prepared by mixing and stirring the components until a uniform dispersion is completed.

EXAMPLE C 8

A formulation having the following composition is prepared:

    ______________________________________                                         (A)    N(2-Propionamido-4-propylthio-phenyl)-                                         N'-N"-bis-methoxy-                                                             carbonyl-guanidine       30%                                            (B)    Polyethylenglycol (6000) 40%                                            (C)    (Polyoxy(40)stearate)    30%                                            ______________________________________                                    

The components (B) and (C) are mixed at 50°-60° C. and then is component A is added by stirring. The formulation is solidified by cooling and ground, without remelting of the polyethylene glycol, to a fine powder.

EXAMPLE C 9

A drenchpowder having the following composition is prepared:

    ______________________________________                                         (A)     The formulation of example C 8                                                                         15 g                                           (B)     colloidal silica        6 g                                            (C)     Carboxymethylcellulose  6 g                                            ______________________________________                                    

The components are blended together until uniform and then are finely powdered.

EXAMPLE C 10

A suspension having the following formulation is prepared:

    ______________________________________                                         (A)    The formulation of example C 8                                                                        7,5 g                                            (B)    citric acid, hydrous   0,43 g                                           (C)    sodium citrat          0,67 g                                           (D)    carboxymethylcellulose 1,1 g                                            (E)    colloidal silica       1 g                                              (F)    sorbic acid            0,3 g                                            (G)    purified water         to 100 ml                                        ______________________________________                                    

The sorbic acid, citric acid and sodium citrate are added to 90 ml of water which has been heated to 80° C. The colloidal silica and carboxymethyl cellulose are then added, with stirring, until uniformly dispersed and fully hydrated. The mixture is cooled to 45° C. and the formulation of Example 8 is added, with stirring, until it is uniformly dispersed. The suspension is cooled to room temperature and the balance of the water is added. 

What is claimed is:
 1. A substituted ophenyldiamine derivative of the formula ##STR61## in which X represents S, SO or SO₂,R represents a straight chain or branched alkyl group of from 1 to 6 carbon atoms, or a straight chain or branched alkenyl or alkinyl group of from 2 to 6 carbon atoms, the alkyl, alkenyl or alkinyl group being unsubstituted or substituted by halogen, cyano, (C₁ -C₄)-alkoxy or (C₁ -C₄)-alkylthio; R¹ and R² are different from one another and individually represent ##STR62## in which R³ and R⁴ represent straight chain or branched alkyl groups of from 1 to 6 carbon atoms, R⁵ represents hydrogen, or a straight chain or branched alkyl group with 1 to 6 carbon atoms or a straight-chain or branched alkoxy group of from 1 to 6 carbon atoms, the alkyl or alkoxy group being unsubstituted or substituted by halogen, cyano, (C₁ -C₆)-alkoxy, (C₁ -C₄)-alkylmercapto, or by a radical of the formula ##STR63## in which R⁶ and R⁷ are identical or different and each represents hydrogen, (C₁ -C₄)-alkyl which is unsubstituted or substituted by (C₁ -C₄)-alkoxy, trifluoromethyl or cyano, orin which the two radicals R⁶ and R⁷, together with the nitrogen atom to which they are attached, form a 5-, 6- or 7-membered pyrrolidinyl, piperidinyl, hexamethyleneiminyl, thiomorpholinyl, piperazinyl or N-methylaminomethyl ringor a salt thereof.
 2. A compound of claim 1 wherein X represents S.
 3. A compound of claim 1 wherein X represents SO.
 4. A compound of claim 1 wherein X represents SO₂.
 5. A compound of claim 1 in the form of a physiologically acceptable salt.
 6. A pharmaceutical composition containing as an active ingredient an anthelmintically effective amount of a compound of claim 1 in admixture with a solid or liquefied gaseous diluent or in admixture with a liquid diluent other than a solvent of a molecular weight less than 200 except in the presence of a surface-active agent.
 7. A pharmaceutical composition containing as an active ingredient an anthelmintically effective amount of a compound of claim 1 in the form of a sterile or isotonic aqueous solution.
 8. A composition of claim 7 containing from 0.5 to 95% by weight of the said active ingredient.
 9. A composition of claim 6 containing from 0.5 to 95% by weight of said active ingredient.
 10. A medicament in dosage unit form comprising an anthelmintically effective amount of a compound of claim 1 and an inert pharmaceutical carrier.
 11. A medicament of claim 10 in the form of tablets, pills, dragees, capsules, ampoules, or suppositories.
 12. A method of combating helminthiases in a warmblooded animal which comprises administering to said animal an anthelmintically effective amount of a compound of claim 1 either alone or in admixture with a diluent or in the form of a medicament.
 13. A method of claim 12 in which the active compound is administered in an amount of 0.1 to 50 mg per kg body weight per day.
 14. A method according to claim 12 in which the active compound is administered orally or parenterally.
 15. Compound having formula ##STR64##
 16. Compound having formula ##STR65##
 17. Compound having formula ##STR66##
 18. Compound having formula ##STR67##
 19. Compound having formula ##STR68##
 20. Compound having formula ##STR69##
 21. Compound having formula ##STR70##
 22. Compound having formula ##STR71##
 23. Compound having formula ##STR72##
 24. Compound having formula ##STR73##
 25. Compound having formula ##STR74##
 26. Compound having formula ##STR75##
 27. Compound having formula ##STR76## 